It is estimated that there will be 14,250 new cases and approximately 13,300 deaths from esophageal cancer in the United States during 2004. Approximately 80% of these tumors will be esophageal adenocarcinoma (EA) and the remaining 20% will be squamous cell carcinoma. The majority, if not all, of EA are thought to arise in patients with Barrett's esophagus (BE), a pre-neoplastic condition caused by metaplasia of the normal squamous mucosa of the distal esophagus into specialized intestinal mucosa containing goblet cells. BE is caused by chronic gastroesophageal reflux disease (GERD), a disorder that affects more than 20 million Americans on a daily basis. Six to fourteen percent of people with chronic GERD will develop BE. The incidence of EA in patients with BE has been reported to be approximately 0.5%-1.0% per year and the lifetime cancer risk for patients with BE is about 5%.
The histologic steps leading to esophageal adenocarcinoma in patients with BE are as follows: 1) intestinal metaplasia (IM) of the normal stratified squamous epithelium, 2) low-grade dysplasia (LGD), 3) high-grade dysplasia (HGD) and 4) EA. Patients diagnosed with BE should undergo regular surveillance for the development of neoplastic lesions, including LGD, HGD, and EA. Patients with EA and HGD must be treated aggressively either with distal esophagectomy or more recently developed therapies such as photodynamic therapy or other ablative techniques to prevent progression to metastatic and incurable disease. Patients with LGD are at risk of progressing to HGD and therefore require regular surveillance but not esophagectomy. The overall 5-year survival for patients with EA is only 20%. Early and accurate detection and treatment of the neoplastic precursors of EA (i.e., IM, LGD, and HGD) will be required if there is to be an increase in the survival rate of patients with BE-associated neoplasia.
Histology results are currently considered the gold standard for determining if a patient has dysplasia and/or EA. It is presently recommended that BE patients be monitored for the development of HGD and EA by performing regular endoscopic examinations of the esophagus and obtaining four-quadrant biopsies for every 1-2 cm of affected esophagus. However, this recommendation is not frequently followed mainly due to the extended length of time needed to perform this procedure, especially on patients with long segment BE. Problems associated with the use of biopsies for monitoring Barrett's patients for the development of neoplasia include: 1) limited sampling of affected mucosa, 2) impracticability of taking four-quadrant biopsies every 1-2 cm, and 3) poor inter-observer reproducibility of pathologists for the diagnosis of LGD and HGD. It has been estimated that endoscopic surveillance protocols that utilize four-quadrant biopsies every cm only sample about 1-2% of the affected mucosa. This limited sampling may lead to false negative pathology results or to under-staging (e.g., pathology results showing only IM or LGD in a patient who has HGD or EA). Thus, there is a need for improved methods and compositions for distinguishing HGD and EA from LGD+IM+normal and LGD from normal+IM patient samples.